An Efficient Method for the In Vitro Production of Azol(in)e-Based Cyclic Peptides

Wael E. Houssen, Andrew F. Bent, Andrew R. McEwan, Nathalie Pieiller, Jioji Tabudravu, Jesko Koehnke, Greg Mann, Rosemary I. Adaba, Louise Thomas, Usama W. Hawas, Huanting Liu, Ulrich Schwarz-Linek, Margaret C. M. Smith, James H. Naismith*, Marcel Jaspars

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

Heterocycle-containing cyclic peptides are promising scaffolds for the pharmaceutical industry but their chemical synthesis is very challenging. A new universal method has been devised to prepare these compounds by using a set of engineered marine-derived enzymes and substrates obtained from a family of ribosomally produced and post-translationally modified peptides called the cyanobactins. The substrate precursor peptide is engineered to have a non-native protease cleavage site that can be rapidly cleaved. The other enzymes used are heterocyclases that convert Cys or Cys/Ser/Thr into their corresponding azolines. A macrocycle is formed using a macrocyclase enzyme, followed by oxidation of the azolines to azoles with a specific oxidase. The work is exemplified by the production of 17 macrocycles containing 6-9 residues representing 11 out of the 20 canonical amino acids.

Original languageEnglish
Pages (from-to)14171-14174
Number of pages4
JournalAngewandte Chemie International Edition
Volume53
Issue number51
DOIs
Publication statusPublished - 15 Dec 2014

Keywords

  • cyanobactins
  • cyclic peptides
  • biosynthesis
  • patellamides
  • ribosomal peptides
  • discovery
  • macrocyclization
  • route

Cite this

Houssen, W. E., Bent, A. F., McEwan, A. R., Pieiller, N., Tabudravu, J., Koehnke, J., Mann, G., Adaba, R. I., Thomas, L., Hawas, U. W., Liu, H., Schwarz-Linek, U., Smith, M. C. M., Naismith, J. H., & Jaspars, M. (2014). An Efficient Method for the In Vitro Production of Azol(in)e-Based Cyclic Peptides. Angewandte Chemie International Edition, 53(51), 14171-14174. https://doi.org/10.1002/anie.201408082